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Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC.

ABSTRACT: Immune checkpoint inhibitor (ICI) treatment has recently become a first-line therapy for many non-small cell lung cancer (NSCLC) patients. Unfortunately, most NSCLC patients are refractory to ICI monotherapy, and initial attempts to address this issue with secondary therapeutics have proven unsuccessful. To identify entities precluding CD8+ T cell accumulation in this process, we performed unbiased analyses on flow cytometry, gene expression, and multiplexed immunohistochemical data from a NSCLC patient cohort. The results revealed the presence of a myeloid-rich subgroup, which was devoid of CD4+ and CD8+ T cells. Of all myeloid cell types assessed, neutrophils were the most highly associated with the myeloid phenotype. Additionally, the ratio of CD8+ T cells to neutrophils (CD8/PMN) within the tumor mass optimally distinguished between active and myeloid cases. This ratio was also capable of showing the separation of patients responsive to ICI therapy from those with stable or progressive disease in 2 independent cohorts. Tumor-bearing mice treated with a combination of anti-PD1 and SX-682 (CXCR1/2 inhibitor) displayed relocation of lymphocytes from the tumor periphery into a malignant tumor, which was associated with induction of IFN-?-responsive genes. These results suggest that neutrophil antagonism may represent a viable secondary therapeutic strategy to enhance ICI treatment outcomes.

SUBMITTER: Kargl J

PROVIDER: S-EPMC6975266 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC.

Kargl Julia J Zhu Xiaodong X Zhang Huajia H Yang Grace H Y GHY Friesen Travis J TJ Shipley Melissa M Maeda Dean Y DY Zebala John A JA McKay-Fleisch Jill J Meredith Gavin G Mashadi-Hossein Afshin A Baik Christina C Pierce Robert H RH Redman Mary W MW Thompson Jeffrey C JC Albelda Steven M SM Bolouri Hamid H Houghton A McGarry AM

JCI insight 20191219 24

Immune checkpoint inhibitor (ICI) treatment has recently become a first-line therapy for many non-small cell lung cancer (NSCLC) patients. Unfortunately, most NSCLC patients are refractory to ICI monotherapy, and initial attempts to address this issue with secondary therapeutics have proven unsuccessful. To identify entities precluding CD8+ T cell accumulation in this process, we performed unbiased analyses on flow cytometry, gene expression, and multiplexed immunohistochemical data from a NSCLC ...[more]

PMID: 31852845

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Project description:Neutrophil to lymphocyte ratio (NLR) has frequently been reported as a significant indicator of systemic inflammation in various medical conditions. The association underlying NLR and outcomes in patients with acute pancreatitis (AP) has not been evaluated after the publication of revised Atlanta classification.This was a single-center retrospective diagnostic accuracy study and a cohort outcome study. From 2009 to 2015, Asian Chinese patients with a diagnosis of AP presented within 72?hours from symptom onset and underwent neutrophil, lymphocyte assessment at presentation were included in this study. The outcomes were the occurrence of persistent organ failure (POF), intensive care unit (ICU) stay >7 days, and in-hospital mortality. The relationships of baseline neutrophil, lymphocyte count, and NLR with outcomes were assessed with multivariate Cox regression model.A total of 974 consecutive AP patients were clinically eligible. The mean neutrophils, lymphocytes, and NLR for the entire population were 10.23?±?4.76??×?10/L, 1.05?±?0.49??×?10/L, and 12.88?±?11.25. Overall, 223 (22.9%) of the patients developed with POF, 202 (20.7%) spent more than 7 days in ICU, and 58 (6.0%) died during hospitalization. The NLR had a superior predictive performance than neutrophils and lymphocytes. Using an NLR cutoff of 11, the area under the curves (AUC) were 0.76 for POF, 0.74 for longer ICU stay, and 0.79 for death during hospitalization. After multivariate analysis, NLR???11 was further identified as an independent prognostic factor (hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.00-1.89; HR 1.44, 95% CI 1.03-2.00; HR 2.75, 95% CI 1.12-6.76; all P value?<?0.05). Following stratification according to quartiles of NLR, positive trends for the association across increasing NLR quartiles and the 3 outcomes were observed (P values for trends across quartiles were 0.007, 0.016, and 0.028, respectively). The adjusted HRs for highest NLR quartile versus the lowest were 2.80 (95% CI 1.42-5.51) (POF), 2.79 (95% CI 1.37-5.70) (ICU?>?7 days), and 2.22 (95% CI 0.49-10.05) (mortality), respectively.Our data show for the first time that an increased NLR is an independent risk factor for POF, longer ICU stay, and in-hospital mortality in AP.

Dataset Information

Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC.

Publications

Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC.

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